Isotretinoin (Formula I), also known as 13-cis-retinoic acid, is a medication used for the treatment of severe acne. It is sometimes used in prevention of certain skin cancers. It is a retinoid, meaning it is derived from vitamin A and is found in small quantities naturally in the body. Oral isotretinoin is marketed under various trade names, most commonly Accutane. It inhibits the sebaceous gland function and keratinization and is used for the treatment of dermatological diseases. It is very effective in very severe and nodulosystic acne and prevents scarring.
As mentioned above, isotretinoin whose structure represented in Formula I, structurally is a highly conjugated molecule consisting of a substituted cyclohexene moiety and a nine carbon polyene side chain with a terminal free carboxyl group. All but the C-13 double bond in the side chain possess cis geometry and therefore known as 13-cis-retinoic acid.
Commercially available β-ionone has been conveniently used for the construction of the cyclohexene portion of isotretinoin. There are ample literatures available for the preparation of isotretinoin exploring various synthetic alternatives. For example by the process described in J. Organic Chemistry, 54, 2620-2628, 1989; J. Chem. Soc. (Comm), 1984-97, 1968; US Patent Application Publication No. 20050192351; and U.S. Pat. No. 4,556,518. Most commonly used process starts from [3-methyl-5(2,6,6-trimethyl-1-cyclohene-1yl-2,4-pentadienyl]-triphenyl-phosphonium)halide, which is condensed with 5-hydroxy-1methyl-2(5-H)-furanone. However, this condensation reaction yields a mixture of isomers of retinoic acid including the 11,13-di-cis-retinoic acid (Formula II), 9,13,-di-cis-retinoic acid (formula III), all-trans-retinoic acid (Formula IV) and 13-cis-retinoic acid (isotretinoin).

To improve the yield of the 13-cis isomer, the above mixture is subjected to isomerization reaction where the undesired isomers are converted to the desired 13-cis-retinoic acid. The isomerization reaction is effected either by use of heavy metal catalysts such as rhodium or palladium (see US Patent Application Publication No. 20050192351 and U.S. Pat. No. 4,556,518) or by photochemical isomerization (see U.S. Pat. No. 6,177,579); however, in the photo-chemical isomerization reaction, the yield of 13-cis-retinoic acid is very low (nearly 44%). The metal catalyzed isomerization reaction provides a higher isomeric conversion in the order of greater than 97%; however, the product obtained is contaminated with the heavy metals (in the order of about 30000-40000 ppm after isolation), which does not meet the required purity for the drug, but also contribute to the known instability of the product (for the instability studies on isotretinoin, see Pharmaceutical Research, 1992, 9:1203-1208).
The crystallization methods so far reported do not effectively remove the trace metals, unless a thorough repeated crystallization from organic solvents is performed, which is not only unacceptable for stability of the compound but also for economy of the process. This is because, the solubility of isotretinoin in organic or aqueous solvents is very low; and as such, very high volume of solvents are required to completely dissolve the trace metal contaminated isotrentioin for crystallization. The higher temperature crystallization removes heavy metal to some extent, but such operations further degrades the product due to instability of isotretinoin under these conditions. Although isotretinoin is soluble in ethers or chlorinated hydrocarbons like methylene chloride, the crystallization from these solvents are not acceptable due to organic volatile impurities (OVI) issues and any further processing for removal of these solvents results in degradation of isotretinoin. Furthermore, it has been reported that the isomeric retinoic acids are rather unstable in organic solvents, which instability is partially due the presence of trace metals. Thus there is a long felt need in the art to get a process for effective removal of trace metals in isotretinoin, while providing stability to the isotretinoin. These objectives are accomplished by the present invention by providing an improved process for isotretinoin objectively for the removal of trace metals.